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JAMA:GWAS在欧洲人群发现 TLR1与H.pylori血清学阳性率相关

2013-05-10 高晓方 编译 中国医学论坛报

    欧洲一项研究通过全基因组关联分析(GWAS)及荟萃分析,确认Toll样受体(TLR)1与幽门螺杆菌(H.pylori)抗体血清学阳性率具有相关性,TLR1遗传变异或将有助于解释不同个体H.pylori感染风险的变化。论文本周发表于《美国医学会杂志》。   本研究在欧洲人群研究队列中[SHIP(n=3830)和RS-Ⅰ、Ⅱ(n=7108)]实施了2项独立GWAS,再行荟萃分析;

TLR1与H.pylori血清学阳性率相关


 

  欧洲一项研究通过全基因组关联分析(GWAS)及荟萃分析,确认Toll样受体(TLR)1与幽门螺杆菌(H.pylori)抗体血清学阳性率具有相关性,TLR1遗传变异或将有助于解释不同个体H.pylori感染风险的变化。论文本周发表于《美国医学会杂志》。

  本研究在欧洲人群研究队列中[SHIP(n=3830)和RS-Ⅰ、Ⅱ(n=7108)]实施了2项独立GWAS,再行荟萃分析;在RS-Ⅲ和SHIP-TREND人群中,分析全血RNA基因表达谱;在SHIP-TREND人群中,分析粪便H.pylori抗原。

  结果显示,在10938受试者中,56.2%为H.pylori血清学阳性。GWAS确认,TLR基因座(4p14;rs10004195;OR 0.70)和FCGR2A基因座(1q23.3;rs368433;OR 0.73)与H.pylori血清学阳性率具有相关性。在位于4p14的3个TLR基因中,仅TLR1存在rs10004195-A次要等位基因每拷贝数差异表达(β=-0.23)。粪便H.pylori抗原滴度较高的个体同样表现为最高四分位TLR1表达。此外,TLR1在胞外域表现出与rs10004195 SNP密切关联的Asn248Ser替换。

  ■ 同期述评

  GWAS时代的H.pylori易感性

  英国阿柏丁大学(Aberdeen University) 艾尔奥马(El-Omar)

  H.pylori感染仍有诸多基础问题有待解答,例如,感染在人与人间传播的准确机制仍不清楚,为何一些个体虽经充分感染暴露但却无细菌定植。

  本期JAMA中,迈勒(Maylerle)等报道了迄今首个也是最佳的GWAS研究,旨在揭示H.pylori易感性的遗传学背景。

  此项研究提供了重要的新资料。概括而言,TLR1(一种先天免疫应答蛋白受体)低表达与H.pylori感染的防护相关,而高表达则与H.pylori血清学阳性及粪便抗原载量升高可能相关。基于这些发现,过多TLR1似乎是不利的,其增加了暴露后获得或感染持续的可能性,尽管具体机制尚不清楚。

  TLR1已知是TLR2的辅助受体,二者形成异二聚体,可被来源于革兰阴性菌细胞壁的脂肽所识别。这一脂肽识别以及后续的免疫级联,可能形成一个抗炎环境,钝化宿主对病原体的炎症反应,以便利于细菌的定植。

  需要注意的是,此项研究仅评估了与H.pylori血清学阳性(当前或既往感染的证据)的相关性,未对定植或症状性疾病加以探讨。在H.pylori感染研究中存在的一个问题是,对H.pylori的暴露未能被确认,尤其是在感染压力较低的西方人群中。因此,在德国或荷兰的H.pylori血清学阴性,可能是因为缺乏暴露而非真正的遗传防护。因而,在解释本研究结果时,必须谨慎。

  本研究的结果,不但需要在欧洲人群中加以验证,也需要在其他族裔中验证,特别是在亚洲、东欧和南美等胃癌高发人群。通过国际性多中心协作研究,进一步阐明H.pylori易感性的遗传学基础,也非常必要。


Identification of Genetic Loci Associated With Helicobacter pylori Serologic Status
Importance 
Helicobacter pylori is a major cause of gastritis and gastroduodenal ulcer disease and can cause cancer. H pylori prevalence is as high as 90% in some developing countries but 10% of a given population is never colonized, regardless of exposure. Genetic factors are hypothesized to confer H pylori susceptibility.
Objective 
To identify genetic loci associated with H pylori seroprevalence in 2 independent population-based cohorts and to determine their putative pathophysiological role by whole-blood RNA gene expression profiling.
Design, Setting, and Participants 
Two independent genome-wide association studies (GWASs) and a subsequent meta-analysis were conducted for anti-H pylori IgG serology in the Study of Health in Pomerania (SHIP) (recruitment, 1997-2001 [n  = 3830]) as well as the Rotterdam Study (RS-I) (recruitment, 1990-1993) and RS-II (recruitment, 2000-2001 [n = 7108]) populations. Whole-blood RNA gene expression profiles were analyzed in RS-III (recruitment, 2006-2008 [n = 762]) and SHIP-TREND (recruitment, 2008-2012 [n = 991]), and fecal H pylori antigen in SHIP-TREND (n = 961).
Main Outcomes and Measures 
H pylori seroprevalence.
Results 
Of 10 938 participants, 6160 (56.3%) were seropositive for H pylori. GWASs identified the toll-like receptor (TLR) locus (4p14; top-ranked single-nucleotide polymorphism (SNP), rs10004195; P = 1.4 × 10−18; odds ratio, 0.70 [95% CI, 0.65 to 0.76]) and the FCGR2A locus (1q23.3; top-ranked SNP, rs368433; P = 2.1 × 10−8; odds ratio, 0.73 [95% CI, 0.65 to 0.81]) as associated with H pylori seroprevalence. Among the 3 TLR genes at 4p14, only TLR1 was differentially expressed per copy number of the minor rs10004195-A allele (β = −0.23 [95% CI, −0.34 to −0.11]; P = 2.1 × 10−4). Individuals with high fecal H pylori antigen titers (optical density >1) also exhibited the highest 25% of TLR1 expression levels (P = .01 by χ2 test). Furthermore, TLR1 exhibited an Asn248Ser substitution in the extracellular domain strongly linked to the rs10004195 SNP.
Conclusions and Relevance 
GWAS meta-analysis identified an association between TLR1 and H pylori seroprevalence, a finding that requires replication in nonwhite populations. If confirmed, genetic variations in TLR1 may help explain some of the observed variation in individual risk for H pylori infection.

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    2013-10-14 智智灵药
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    2013-05-12 lxg951
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